Genomic analysis to identify determinants of inherent response and resistance to elranatamab in MagnetisMM-3 cohort A.
Authors: Nizar J. Bahlis, Hang Quach, Katja Weisel, Andrea Viqueira, Shen-Wu Wang, Phineas T. Hamilton, Tao Xie, Thomas O'Brien, Paula Rodríguez-Otero
Journal: Journal of Clinical Oncology (2023)

8045 Background: MagnetisMM-3 (NCT04649359) is an open-label, multicenter, non-randomized phase 2 study of elranatamab monotherapy in patients (pts) with multiple myeloma refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug and 1 anti-CD38 antibody. This analysis examined molecular correlates of elranatamab response and resistance in pts naïve to B-cell maturation antigen (BCMA)-directed therapy (Cohort A). Methods: Bone marrow aspirate (BMA) samples collected at screening were analyzed by whole exome and whole transcriptome sequencing. To investigate the contribution of the tumor microenvironment (TME) in elranatamab response, the abundance of cell types in the BMA samples collected at screening was estimated using single sample gene set enrichment analysis (ssGSEA) of LM22 cell type signatures. Response was defined as a best overall response of very good partial response or better (partial response was considered non-response for this analysis). Results: TNFRSF17 (BCMA encoding gene) expression correlated with markers of disease burden: levels increased with disease stage (with progressively higher levels in R-ISS stages I, II, and III; p= 0.014), were higher in pts with high-risk cytogenetics ( p= 0.002) and correlated with plasma cell content in BMA samples ( ρ= 0.80; p&lt; 10 -10 ). TNFRSF17 expression trended higher in non-responders ( p= 0.08), but this trend was diminished when adjusting for disease burden. These findings suggest TNFRSF17 expression in bulk BM samples is associated with higher disease burden and likely poorer response. According to ssGSEA of LM22 cell types, plasma cells in BMA were associated with non-responders ( p= 0.03). Further multivariable modeling (controlling for plasma cell content) revealed additional cell types associated with response, including macrophages and monocytes, which were associated with poor outcome. Pts with both low plasma and low myeloid cells were most likely to respond. Genome wide copy number analysis showed that TNFRSF17 locus amplification was associated with non-response ( p= 0.008). Chromosomal alterations associated with non-response were identified, including genomic loci known to define high-risk MM (eg, 1q21+) and loci not known to be associated with high-risk MM (eg, 17q21+ and 6p21+). Conclusions: Genomic analysis of BMA samples from MagnetisMM-3 identified an association between higher TNFRSF17 expression in the TME and unfavorable outcomes, likely due to its surrogacy with increased tumor burden. Features of high-risk disease were also associated with lack of response to elranatamab. Adjusting for tumor cell content revealed additional aspects of the TME associated with poor response, including increased myeloid cell populations. Lastly, alterations in specific genomic loci were also associated with response, consistent with tumor intrinsic features influencing elranatamab response. Clinical trial information: NCT04649359 .